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WO2019156999A1 - Inhibiteurs de mtor topiques pour des affections prolifératives et vasculaires cutanées - Google Patents

Inhibiteurs de mtor topiques pour des affections prolifératives et vasculaires cutanées Download PDF

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Publication number
WO2019156999A1
WO2019156999A1 PCT/US2019/016758 US2019016758W WO2019156999A1 WO 2019156999 A1 WO2019156999 A1 WO 2019156999A1 US 2019016758 W US2019016758 W US 2019016758W WO 2019156999 A1 WO2019156999 A1 WO 2019156999A1
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syndrome
cutaneous
certain embodiments
mtor
mtor inhibitor
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PCT/US2019/016758
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English (en)
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Cynthia Marie Carver DEKLOTZ
Robert A. SILVERMAN
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Georgetown University
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Priority to US16/967,457 priority Critical patent/US12109199B2/en
Publication of WO2019156999A1 publication Critical patent/WO2019156999A1/fr
Priority to US18/824,474 priority patent/US20240423963A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • Sirolimus inhibits the am alian target of rapamycin (mTOR), which is a serine/threonine protein kinase whose activity has been reported to lead to cell proliferation, cytokine production, and angiogenesis.
  • mTOR am alian target of rapamycin
  • Orally administered rapamycin is approved for systemic use in a variety of clinical applications. However, there is no standard or commercially available topical formulation.
  • compositions useful for treating any of a variety of cutaneous proliferative conditions and cutaneous vascular conditions by topical administration of an mTOR inhibitor are provided.
  • An aspect of the invention is a method of treating a cutaneous proliferative condition, comprising topically administering to an affected area of a subject in need thereof a therapeutically effective amount of a mammalian target of rapamycin (mTOR) inhibitor, thereby treating the condition.
  • mTOR mammalian target of rapamycin
  • the cutaneous proliferative condition excludes any one or more of trichoepithelioma and familial multiple discoid fibroma.
  • the cutaneous proliferative condition is selected from the group consisting of histiocytosis, Langerhans cell histiocytosis, histiocytosis X, eosinophilic granuloma, Letterer-Siwe disease, Hand-Schuller-Christian syndrome, Hashimoto-Pritzker syndrome, non-Langerhans cell histiocytosis (non-LCH), benign cephalic histiocytosis (BCH), juvenile xanthogranuloma, xanthoma disseminatum, necrobiotic xanthogranuloma, generalized eruptive histiocytoma, progressive nodular histiocytoma, indeterminate cell histiocytosis, multicentric reticulohistiocytosis, sinus histiocytosis with massive lymphadenopathy, scars, hypertrophic scars, keloids, Proteus syndrome, PTEN
  • PI3K/AKT/mTOR mutations keratoderma, acanthosis nigricans, Birt-Hogg-Dube syndrome, Brooke- Spiegler syndrome, cylindromas, and epidermal nevi.
  • the cutaneous proliferative condition is Langerhans cell histiocytosis (LCH).
  • the cutaneous proliferative condition is non-Langerhans cell histiocytosis (non-LCH).
  • the cutaneous proliferative condition is benign cephalic histiocytosis (BCH).
  • the affected area comprises at least a portion of any one or more of the head, face, and neck.
  • the mTOR inhibitor is selected from the group consisting of sirolimus, everolimus, and a combination thereof. In certain embodiments, the mTOR inhibitor is sirolimus. In certain embodiments, the mTOR inhibitor is everolimus.
  • the mTOR inhibitor inhibits only mTORC 1 activity. In certain embodiments, the mTOR inhibitor inhibits only mTORC2 activity. In certain embodiments, the mTOR inhibitor inhibits both mTORC 1 and mTORC2 activity.
  • the mTOR inhibitor is provided as a topical formulation comprising 0.01% to 10% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation comprising 0.05% to 5% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation comprising 0.1% to 2% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided in combination with a PI3K inhibitor.
  • the mTOR inhibitor is provided as a combination mTOR/PI3K dual inhibitor.
  • the subject is a human less than 18 years of age.
  • the subject is a human at least 18 years of age.
  • An aspect of the invention is a method of treating a cutaneous vascular condition, comprising topically administering to an affected area of a subject in need thereof a therapeutically effective amount of a mammalian target of rapamycin (mTOR) inhibitor, thereby treating the condition.
  • mTOR mammalian target of rapamycin
  • the cutaneous vascular condition excludes any one or more of facial angiofibromas in tuberous sclerosis, microcystic lymphatic malformations, and port wine stains.
  • the cutaneous vascular condition is selected from the group consisting of PIK3CA-related overgrowth spectrum (PROS), venolymphatic
  • CM-AVM cutaneous capillary malformation-arteriovenous malformation
  • the cutaneous vascular condition is PIK3CA-related overgrowth spectrum (PROS).
  • PROS PIK3CA-related overgrowth spectrum
  • the cutaneous vascular condition is venolymphatic malformations.
  • cutaneous conditions that have a vascular or proliferative aspect to them include acne rosacea, periorificial dermatitis, acne vulgaris, scars, hypertropic scars, and keloidal scars.
  • the affected area comprises at least a portion of any one or more of the head, face, and neck.
  • the mTOR inhibitor is selected from the group consisting of sirolimus, everolimus, and a combination thereof. In certain embodiments, the mTOR inhibitor is sirolimus. In certain embodiments, the mTOR inhibitor is everolimus.
  • the mTOR inhibitor inhibits only mTORC 1 activity. In certain embodiments, the mTOR inhibitor inhibits only mTORC2 activity. In certain embodiments, the mTOR inhibitor inhibits both mTORC 1 and mTORC2 activity.
  • the mTOR inhibitor is provided as a topical formulation comprising 0.01% to 10% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation comprising 0.05% to 5% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable earner. In certain embodiments, the mTOR inhibitor is provided as a topical formulation comprising 0.1% to 2% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided in combination with a PI3K inhibitor.
  • the mTOR inhibitor is provided as a combination mTOR/PI3K dual inhibitor.
  • the subject is a human less than 18 years of age.
  • the subject is a human at least 18 years of age.
  • rapamycin also known as the mechanistic target of rapamycin and FK506-binding protein l2-rapamycin-associated protein 1 (FRAP1)
  • mTOR rapamycin
  • FRAP1 FK506-binding protein l2-rapamycin-associated protein 1
  • PI3K phosphatidylinositol-3 -kinase
  • PIKKs phosphatidylinositol-3 -kinase
  • Members in this family are large in size (>2,500 amino acids) and harbor a kinase domain at their C-terminals that shares sequence similarity to phosphatidylinositol-3 -kinase (PI3K).
  • mTOR is a protein kinase that phosphorylates threonine and serine residues in its substrates.
  • mTOR serves as the catalytic subunits of two multi-protein complexes termed as the mTOR complex 1
  • mTORCl complex 2
  • TORC1 is a major downstream component of the PI3K/AKT pathway that relays the signals from tumor suppressors PTEN, LKB1 and TSC1/2, and oncoproteins PI3K and AKT.
  • mTORCl controls cellular biogenesis through regulation of protein synthesis and turnover. It phosphorylates eIF4E binding protein 1 (4EBP1) and ribosomal protein S6 kinase (S6K), two factors involved in translation initiation. Its activity controls protein turnover through repressing autophagy.
  • mTORC2 is also involved in the PI3K/AKT pathway but its function is independent of mTORC 1. It phosphorylates and stimulates AKT activation, and hence plays a critical role in AKT mediated cell survival.
  • mTOR Inhibitors eIF4E binding protein 1 (4EBP1) and ribosomal protein S6 kinase
  • an“mTOR inhibitor” refers to an agent that can reduce the expression and/or activity of mTOR, including association of mTOR with its substrates.
  • mTOR inhibitors including sirolimus and everolimus, are known and in clinical use.
  • Sirolimus also known as rapamycin
  • Sirolimus is the prototype of the first generation of mTOR inhibitors. It is a macrocyclic lactone that contains two binding moieties that are essential for its action. One moiety binds to FKBP12, a small cytosolic protein that displays peptidylprolyl isomerase activity.
  • rapamycin imposes no significant effect on the function of FKBP12, but binding with FKBP12 allows it to interact with its mechanistic target, mTOR, to form a ternary complex.
  • the rapamycin-FKBPl2 dimer binds to mTOR in a region (FKBPl2-rapamycin binding domain) that is outside of the kinase domain. As such, the binding itself does not inhibit the kinase activity of mTOR. It is believed that the binding interferes with the association of the kinase with its substrates, although the precise mechanism remains to be elucidated.
  • rapamycin only inhibits mTORCl activity.
  • sirolimus and everolimus bind to FK binding protein (FKBP) and are believed to modulate the activity of mTOR.
  • FKBP FK binding protein
  • the mTOR inhibits interleukin-2 (IL-2)-mediated signal transduction, resulting in cell-cycle arrest in the Gl-S phase.
  • IL-2 interleukin-2
  • Sirolimus and everolimus block the response of T- and B-cell activation by cytokines, which prevents cell-cycle progression and proliferation.
  • tacrolimus and cyclosporine work by other mechanisms to inhibit the production of cytokines.
  • Sirolimus was first developed into an immunosuppressive drug for its potent action in blocking T-cell activation. It was approved by the FDA in 1997 for use in
  • Rapamycin is poorly water soluble, which affects its bioavailability.
  • Everolimus is the 40- 0-(2-hydroxy ethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mTOR. It is currently used as an
  • Temsirolimus is a derivative and prodrug of sirolimus. It is formulated as an intravenous drug approved for use in the treatment of renal cell carcinoma.
  • Ridaforolimus (AP23573, MK-8669), also known as deforolimus, is an
  • mTOR inhibitors can include so-called second generation mTOR inhibitors.
  • Second generation mTOR inhibitors are known as ATP-competitive mTOR kinase inhibitors. Zaytseva Y. et al., Cancer Letters 319(1): 1-7 (2012).
  • mTORCl/mTORC2 dual inhibitors are designed to compete with ATP in the catalytic site of mTOR. They inhibit all of the kinase-dependent functions of mTORC 1 and mTORC2 and therefore, block the feedback activation of PI3K/AKT signaling, unlike rapalogs that only target mTORC 1. These types of inhibitors have been developed and several of them are being tested in clinical trials.
  • rapalogs Like rapalogs, they decrease protein translation, attenuate cell cycle progression, and inhibit angiogenesis in many cancer cell lines and also in human cancer. In fact they have been proven to be more potent than rapalogs.
  • a“cutaneous proliferative condition” refers to refers to a skin condition characterized by abnormal or undesirable proliferation of principally non- vascular structures or non- vascular tissue in skin.
  • “skin” refers to any or all of epidermis, dermis, and hypodermis, and appendages, glands, and blood and lymphatic vessels therein. See, for example, Bloom and Fawcett, A Textbook of Histology, 10 th Ed., W.B. Saunders, Philadelphia, 1975.
  • the skin condition characterized by abnormal or undesirable proliferation of principally non- vascular structures or non- vascular tissue in skin can be a cutaneous manifestation of a multisystemic or more general condition that is not confined to skin.
  • any cutaneous vascular condition as defined herein is considered to be, or can be considered to be, a cutaneous proliferative condition
  • such cutaneous vascular condition is to be understood also to be included among cutaneous proliferative conditions in accordance with the invention.
  • Cutaneous proliferative conditions include, without limitation, various forms of histiocytosis, hypertrophic and keloidal scars, Proteus syndrome, PTEN hamartoma tumor syndromes, Cowden syndrome, Babbayan-Riley-Ruvalcaba syndrome, cutaneous malignancies and tumors associated with PI3K/AKT/mTOR mutations, keratodermas, acanthosis nigricans, Birt-Hogg-Dube syndrome and its related tumors, Brooke-Spiegler syndrome, cylindromas, and epidermal nevi.
  • the cutaneous proliferative condition excludes any one or more of trichoepithelioma and familial multiple discoid fibroma.
  • Somatic activating mutations in the PI3K/AKT/mTOR pathway have been implicated in numerous conditions, including Proteus syndrome (caused by a somatic gain of function mutation in AKT1) and PIK3CA-Related Overgrowth Spectrum (PROS). As these are due to overactivation of the PI3K/AKT/mTOR pathway, treatment with an mTOR inhibitor to decrease that overactivation would be expected to be effective. Due to this direct pathway involvement and favorable results of studies disclosed in the Examples herein, the inventor expects that the cutaneous features in these syndromes will respond to treatment with topical mTOR inhibitor such as topical rapamycin.
  • topical mTOR inhibitor such as topical rapamycin.
  • Negative regulators of the PI3K/AKT/mTOR signaling pathway include PTEN and TSC1/TSC2 (found in Tuberous Sclerosis Complex). Loss-of function mutations in PTEN are known to cause PTEN hamartoma tumor syndromes, including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, both of which have specific cutaneous findings.
  • Somatic mutations in this pathway are also linked with several tumors and malignancies. If such tumors and malignancies are limited to the skin and soft tissue, the inventor expects that topical mTOR inhibitor such as topical rapamycin will be effective in the treatment of those tumors and cutaneous malignancies.
  • topical mTOR inhibitor such as topical rapamycin
  • “histiocytosis” refers to disorders that are characterized by infiltrates containing either Langerhans cell histiocytes (the X-type histiocytoses) or non- Langerhans cell histiocytes (the non-X or non-LCH histiocytoses).
  • JXG juvenile xanthogranuloma
  • SHML multicentric reticulohistiocytosis and sinus histiocytosis with massive lymphadenopathy
  • LCH Langerhans Cell Histiocytosis
  • “Langerhans cell histiocytosis” refers to a clonal proliferative disease of Langerhans cells that express an immunophenotype positive for S 100, CD 1 a and Langerin (CD207), and which contain cytoplasmic Birbeck granules. Because Langerin is the major protein of Birbeck granules, Langerin immunostaining can be used as a substitute for demonstration of Birbeck granules by electron microscopy. LCH represents a disease spectrum with four prominent but overlapping syndromes: Letterer-Siwe disease; Hand-Schuller-Christian disease;
  • eosinophilic granuloma eosinophilic granuloma
  • congenital self-healing reticulohistiocytosis also known as Hashimoto-Pritzker disease or Hashimoto-Pritzker syndrome.
  • Disease expression ranges from mild, sometimes asymptomatic, single-organ involvement to severe, progressive multisystem disease.
  • LCH occurs worldwide and most commonly develops in children ages 1-3 years, though disease can develop at any age. The reported incidence of LCH varies widely. However, an annual incidence of at least five per million children is often quoted, with the adult incidence suspected to be less than one-third that of children. LCH is more common in boys, with a male : female ratio of nearly 2 : 1. In adults, there may be a slight female predominance. At least a small subset of LCH appears to be hereditary.
  • LCH clonal neoplastic disorder
  • cytokines in lesions of patients with LCH, including TNF-a, interferon-g, granulocyte-monocyte colony-stimulating factor (GM-CSF) and interleukin (IL)-l, IL-2, IL-4 and IL-10; these cytokines and interleukins are thought to promote various disease-related symptoms and morbidity, rather than being responsible for the development of disease.
  • GM-CSF granulocyte-monocyte colony-stimulating factor
  • IL interleukin
  • corticosteroids topical antimicrobials
  • narrowband UVB narrowband UVB
  • PUVA psoralen and long-wave ultraviolet (UVA) radiation
  • mechlorethamine topical nitrogen mustard
  • Symptomatic recurrent or new lesions or those with a significant risk of fracture, cosmetic defect or functional abnormality, may require treatment with radiation.
  • Treatment options for less problematic bone tumors include oral nonsteroidal anti-inflammatory drugs (NSAIDs) and intralesional corticosteroid injections.
  • NSAIDs oral nonsteroidal anti-inflammatory drugs
  • corticosteroid injections intralesional corticosteroid injections.
  • Multisystem disease has traditionally been treated with systemic therapy.
  • the LCH- 1 clinical trial compared the effectiveness of vinblastine versus etoposide (in combination with a single dose of methylprednisolone).
  • the vinblastine- and etoposide-based regimens were found to be equivalent with regard to disease response (58% vs. 65%, respectively), reactivation (61% vs. 55%), toxicity (47% vs. 58%), and survival (76% vs. 83%), as well as in prevention of disease-related permanent consequences such as diabetes insipidus, endocrinopathies (e.g. growth hormone deficiencies), orthopedic problems, hearing impairment, liver and lung failure, and CNS disease.
  • hematopoietic stem cell liver or lung transplantation may be required.
  • Letterer-Siwe Disease - Letterer-Siwe disease is the acute diffuse form of LCH. It is a multisystem disease that nearly always develops prior to age 2 years, commonly presenting in children less than 1 year of age. Cutaneous involvement occurs in most patients as 1-2 mm pink to skin-colored papules, pustules and/or vesicles in the scalp, flexural areas of the neck, axilla and perineum, and on the trunk. Scale and crust with secondary impetiginization are common changes, as is the development of petechiae and purpura. The lesions tend to coalesce and become tender, especially when fissures develop in intertriginous zones almoplantar and nail involvement can occur, as can soft tissue nodules.
  • Hand-Schuller-Christian Disease represents the triad of diabetes insipidus, bone lesions and exophthalmos. These patients tend to have a chronic progressive course. For most, Hand-Schuller-Christian disease begins between the ages of 2 and 6 years. Patients with the complete triad are rare, as exophthalmos is uncommon and often a late finding. Approximately 30% of patients develop skin or mucous membrane lesions. While early cutaneous lesions are similar to those seen in Letterer-Siwe disease, older lesions can become xanthomatous. Ulcerative nodules may develop in the oral and genital areas, with premature loss of teeth possible secondary to gingival lesions.
  • the chances of reversing the diabetes insipidus with radiation or chemotherapy are remote once symptoms develop.
  • symptomatic treatment with vasopressin has been found to be effective in treating the diabetes insipdus.
  • Eosinophilic Granuloma is a localized variant of LCH that generally affects older children, boys more than girls. Skin and mucous membrane lesions are rare, with a single asymptomatic granulomatous lesion of the bone the most common manifestation. The cranium is most frequently affected, although lesions can also develop within the ribs, vertebrae, pelvis, scapulae, and long bones. A spontaneous fracture or otitis media may be the first sign of disease.
  • Hashimoto-Pritzker Syndrome Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease or syndrome) is a variant of LCH which is generally limited to the skin and rapidly self-healing. It presents at birth or in the first few days of life with a characteristic eruption of widespread red to purplish-brown papulonodules. After several weeks, the lesions crust and involute. Solitary papules or nodules (often eroded or ulcerated) and disseminated vesicular eruptions have also been observed. Mucous membrane lesions are rare, although systemic involvement has been reported. While congenital self-healing reticulohistiocytosis is considered a benign, self-resolving disorder, its relationship to other LCH variants suggests a cautious approach with respect to prognosis.
  • Non-Langerhans Cell Histiocytosis (non-LCH) -
  • “non-Langerhans cell histiocytosis (non-LCH)” refers to the non-X histiocytoses.
  • Non-X histiocytoses are divided clinically into three groups: those involving primarily or only the skin (e.g., JXG); those that affect the skin but have a major systemic component (e.g., Erdheim-Chester disease); and those that are primarily a systemic disease with occasional skin lesions as a part of the disease (e.g., sinus histiocytosis with massive lymphadenopathy, SHML).
  • JXG JXG, Erdheim-Chester disease, generalized eruptive histiocytosis, xanthoma disseminatum, and progressive nodular histiocytosis.
  • Most diseases at the beginning of the spectrum are localized benign disorders. As one progresses through the diseases they tend to become more generalized but are still benign, and at the end of the spectrum lie diseases that are less likely to involute and may have visceral involvement. In any of these diseases, many morphologies of the histiocyte may be seen.
  • Benign Cephalic Histiocytosis refers to a rare skin condition typically seen in young children between a few months of age up to several years old. The disease begins initially on the head in virtually all cases, often the cheeks, eyelids, forehead, and ears. Lesions may later appear on the neck and upper trunk, and less commonly more caudad. Occasionally, they can be more generalized in distribution. There are nearly always multiple lesions, but often few in number (5-20), although they can number more than 100. Individual lesions are slightly raised, reddish-yellow papules, 2-4 mm in diameter. Lesions may coalesce to give a reticulate appearance.
  • the lesions cause no symptoms.
  • the mucosa and viscera are not involved.
  • Lesions spontaneously involute over 2-8 years, leaving behind hyperpigmented macules.
  • Some cases of BCH have evolved to become JXGs, and one patient later developed generalized eruptive histiocytoma many years after the involution of BCH. This supports the concept outlined above that these conditions may lie along a spectrum and all derive from the same cell type, a dermal dendritic cell. Histologically, there is a diffuse dermal infiltration of monomorphous macrophages, which stain positively for CD68 and factor XHIa and negatively with S 100 and CD 1 a.
  • Juvenile Xanthogranuloma As used herein,“juvenile xanthogranuloma” (JXG) refers to the most common non-LCH. About 1/3 of lesions are congenital and the majority of lesions are diagnosed within the first year of life, but can occur in adulthood. Most lesions are solitary, but they can be multiple. Typically, a JXG begins as a well- demarcated, round to oval papule or nodule and appears pink to red with a yellow tinge, becoming yellow-tan-brown over time.
  • Touton giant cells are characteristic of JXG but not specific for it.
  • the inflammatory infiltrate consists of lymphocytes, eosinophils, and neutrophils, and lacks plasma cells. Fibrosis occurs in the older lesions.
  • the cells of JXG of all anatomic locations stain with factor XHIa, vimentin, fascin, MS-l, and CD68, not with CD1, S100, or other specific markers for Langerhans cells.
  • lymphohistiocytosis syndrome Locally aggressive tumors may be radiated. Systemic steroids, chemotherapy, and even liver or bone marrow transplantation may be required. Even more rarely, a visceral lesion may behave malignantly, spreading to previously unaffected organs and killing the patient.
  • JXGs have been reported in association with neurofibromatosis (NF-l) and juvenile myelomonocytic leukemia (JMML). Patients with NF-l and JXG are 20-32 times more likely to develop JMML.
  • JXG is a proliferation of dermal dendrocytes and LCH is a proliferation of Langerhans cells.
  • JXGs are negative for the Langerhans cell marker CD1. Unlike LCH, JXGs are usually negative for S100, although a few S lOO-positive JXGs have been reported.
  • xanthoma disseminatum refers to a very rare, potentially progressive non-LCH that preferentially affects males in childhood or young adulthood. It is characterized by the insidious onset of small, yellowish-red to brown papules and nodules that are discrete and disseminated. They characteristically involve the eyelids and flexural areas of the axillary and inguinal folds, and the antecubital and popliteal fossae. Over years the lesions increase in number, forming coalescent xanthomatous plaques and nodules.
  • Disseminated xanthosiderohistiocytosis is a variant of XD in which there is a keloidal consistency to the lesions; they have annular borders, a cephalad distribution, and extensive iron and lipid deposition in the macrophages and connective tissue. Progressive XD can produce considerable morbidity and can even be fatal. Therefore, aggressive therapy may be indicated. Systemic steroids have led to improvement in one case. In a patient with XD and dyslipidemia, the combination of rosiglitazone, simvastatin, and acipimox led to partial remission and stabilization of mucosal and osseous disease.
  • Cyclophosphamide has led to dramatic improvement in two of three patients so treated.
  • Necrobiotic Xanthogranuloma refers to a disease with prominent skin findings. The cause is unknown and disease can be progressive. The most common site affected is the periorbital area (65-80% of cases). Multicentric involvement is typical. Characteristic skin lesions are yellow (xanthomatous) plaques and nodules. Periorbitally, they may be mistaken for xanthelasma, but they are deep, firm, and indurated, and may extend into the orbit. The trunk and proximal extremities may have orange-red plaques that have an active red border and an atrophic center with superficial telangiectasias.
  • plaques may grow to 25 cm in diameter.
  • the skin lesions ulcerate in 50% of cases, leading to atrophic scarring.
  • Acral nodules may also occur, some localized solely to the subcutaneous tissue. Extracutaneous involvement most commonly affects the eyes. Patients may complain of burning, itching, or pain around or in the eyes. Diplopia and inflammation in various compartments of the eye can occur, including conjunctivitis, keratitis, scleritis, uveitis, ulceris, ectropion, or proptosis. Ulceration and scarring of the plaques and distortion of the eye may lead to visual occlusion.
  • Thrombocytopenia, neutrophilia, neutropenia, and eosinophilia may be present.
  • the bone marrow may show leukopenia, plasmacytosis (25-50% of patients), or frank myeloma (10- 20% of patients).
  • a myelodysplastic syndrome may be present or develop (chronic lymphocytic lymphoma, Hodgkin or non-Hodgkin lymphoma).
  • the necrobiotic xanthogranuloma predates the development of the myeloma or myelodysplastic syndrome by an average of 2.5 years. Histologically, there are extensive zones of degenerated collagen surrounded by palisaded macrophages.
  • These macrophages are of various forms— foamy, Touton cells, epithelioid, and giant cells, sometimes with more than 50 nuclei.
  • Atypical multinucleated giant cells with multiple nuclei clustered at one end of the cell (polarized nuclei) are seen in 80% or more of cases.
  • the process extends into the fat, obliterating fat lobules. Cholesterol clefts and extracellular lipid deposits are prominent. Within this process is a perivascular and interstitial infiltrate of lymphocytes and plasma cells. Lymphoid follicles are present. In the skin, the lymphoid aggregates are polytypic.
  • the histologic differential diagnosis includes necrobiosis lipoidica and other histiocytoses.
  • Necrobiotic xanthogranuloma has more atypical and Touton giant cells, lymphoid nodules, and cholesterol clefts.
  • GSH Generalized Eruptive Histiocytoma
  • GSH generalized eruptive histiocytoma
  • a rare disease usually presenting in young adulthood, characterized by widespread, erythematous, essentially symmetrical papules, particularly involving the trunk and proximal extremities, sparing the flexors, and rarely involving the mucous membranes (there is no visceral involvement); progressive development of new lesions, often in crops, over several years with eventual spontaneous involution to hyperpigmented macules; and a benign histologic picture of monomorphous, vacuolated macrophages.
  • GEH ulcerative colitis
  • GEH is rare in childhood. In adults and children, GEH may suddenly appear several weeks following a bacterial or viral illness; in adults it may be associated with underlying malignancy, usually leukemia or lymphoma.
  • GEH is distinguished from xanthoma disseminatum by the lack of visceral disease, the benign course, and by the scalloped appearance of the macrophages in xanthoma disseminatum. Histologically, there is a dermal infiltrate of monomorphous vacuolated macrophages and mononuclear histiocytes.
  • the GEH cells stain positively for vimentin, CD68, and usually factor XHIa, and negatively for S 100, and CD 1 a.
  • the natural history of GEH is unpredictable, with complete resolution in some cases and persistence in others. Some cases have progressed to widespread xanthogranulomas, xanthoma disseminatum, or progressive nodular histiocytosis. In childhood, no treatment may be required. In adulthood, treatment with PUVA or isotretinoin may be considered.
  • Progressive Nodular Histiocytoma refers to a variant characterized by a widespread eruption of hundreds of yellow-brown, 2-10 mm papules and deeper, larger subcutaneous nodules. Conjunctival, oral, and laryngeal lesions may occur. The face typically is heavily involved with numerous coalescent lesions, which may result in a leonine appearance. New lesions progressively occur, and ulceration is common. Occasionally, bleeding may occur within the subcutaneous nodules, resulting in marked pain.
  • ICH Indeterminate Cell Histiocytosis -
  • “indeterminate cell histiocytosis” refers to rare disorders characterized by lesions that are composed of cells that immunophenotypically stain as Langerhans cells but lack Birbeck granules. Since electron microscopy is rarely employed, it is difficult to use this criterion to establish the diagnosis of a disorder. Langerin immunostaining might be substituted. S100 staining is variable in the various non-Langerhans cell histiocytoses (NLCH), making S100 positivity a soft criterion to use. In addition, reactive conditions are associated with tissue infiltration by S lOO-positive cells.
  • Indeterminate cells may be found as a minor component of the dermal infiltrate in nodular scabies and rarely following pityriasis rosea. Both children and adults are affected by ICH, with males outnumbering females. Solitary and multiple lesions may occur, and the color of lesions varies from yellow to red-brown. Lesions may be papules, plaques, or nodules from 3 mm to 10 cm in size. These clinical features are not specific, and resemble the papular lesions seen in many forms of NLCH. Conjunctival involvement has been reported. Solitary malignant tumors with similar immunohistochemistry have been described, clinically resembling atypical fibroxanthoma.
  • Multicentric Reticulohistiocytosis As used herein,“multicentric
  • reticulohistiocytosis refers to a rare systemic disorder of unknown cause. It is characterized by cutaneous lesions and a destructive arthritis, and is seen almost exclusively in adults, with rare reports of pediatric disease. The skin lesions present as firm red-brown papules, most often distributed on the hands, fingers, lips, ears, and nose. Facial disfigurement may occur, with cartilaginous destruction and the appearance of a leonine facies.
  • The“coral bead” sign refers to the presence of a chain of papules along the cuticle. Nodular lesions on the arms, elbows, and knees may occur and at times resemble rheumatoid nodules. Mucous membrane involvement may occur in up to one-half of patients.
  • Joint involvement is the presenting sign in more than half of patients and is highly destructive. It may involve any joint, especially the interphalangeal joints, and co existing synovitis is common. Shortening of the digits may occur with a“telescopic” or “opera-glass” deformity. Rheumatoid arthritis may be mistakenly diagnosed in some patients. Microscopic examination of skin, bone, or synovial tissue reveals a characteristic histiocytic process, with multinucleated giant cells and a“ground-glass” appearance.
  • Visceral involvement may include pleural effusion, pericarditis, heart failure, salivary gland enlargement, muscle weakness, lymphadenopathy, and gastric ulcer.
  • Multicentric reticulohistiocytosis may regress spontaneously over 6-8 years, but for many patients the articular destruction results in permanent joint deformities. The response of this disorder to therapy is frequently disappointing, with current treatments including non-steroidal antiinflammatory agents, corticosteroids, cyclophosphamide, chlorambucil, methotrexate, hydroxychloroquine, and interferon.
  • Sinus Histiocytosis with Massive Lymphadenopathy refers to a rare disorder of reactive proliferation of histiocytes in the sinuses of lymph nodes. It occurs primarily in children, who present with massive lymphadenopathy, especially cervical. Extranodal involvement may occur, and when it does, the skin is one of the more common organs to be involved. Papules and nodules are the most common skin lesions, and purely cutaneous SHML may occasionally occur. The lesions often involute spontaneously. There are isolated reports of patients with both SHML and lymphoma.
  • Hypertrophic Scars refers to a form of abnormal wound healing characterized by local fibroblast proliferation and excessive collagen production in response to cutaneous injury. Compared to normal skin and normal scars, both hypertrophic scars and keloids have increased cellularity, vascularity and connective tissue. Hypertrophic scars are raised and confined to the wound margin, that is, in contrast to keloids, they remain confined to the site of the original injury. Sometimes hypertrophic scars improve spontaneously and tend to have a good response to treatment. Both transforming growth factor (TOK)-b and platelet-derived growth factor (PDGF) have been shown to play an integral role in wound healing.
  • TOK transforming growth factor
  • PDGF platelet-derived growth factor
  • the majority of cells involved in wound healing express TGF-b in an initially inactive form (which becomes active following its release from the latency associated protein) that strongly promotes the chemotaxis of fibroblasts to the site of injury.
  • TGF-b in an initially inactive form (which becomes active following its release from the latency associated protein) that strongly promotes the chemotaxis of fibroblasts to the site of injury.
  • hypertrophic scars there is an increase in both the number of fibroblasts and density of collagen fibers within the dermis.
  • the orientation of both the cells, which are spindle-shaped, and the collagen becomes parallel to the skin surface.
  • Dermal blood vessels are vertically oriented (i.e., perpendicular to the skin surface), and there may be a sparse perivascular inflammatory infiltrate.
  • Elastic tissue is diminished or absent.
  • a-smooth muscle actin stain a-smooth muscle actin stain to identify myofibroblasts.
  • a-SMA a-smooth muscle actin
  • the overlying epidermis is smooth, glossy, and thinned from pressure.
  • the early, growing lesion is red and tender, and has the consistency of rubber. It is often surrounded by an erythematous halo, and the keloid may be telangiectatic. Lesions may be tender, painful, and pruritic, and may rarely ulcerate or develop draining sinus tracts. Keloids may be distinguished from hypertrophic scars by their clawlike projections and their lack of spontaneous improvement over a period of months.
  • TGF-b which is known to play a critical role in fibroblast proliferation and collagen production, is overproduced and poorly regulated via autocrine signaling pathways.
  • keloidal fibroblasts have increased expression of growth factor receptors, including for TGF-b and PDGF, and therefore respond more intensely to these growth factors. Decreased production of molecules that promote matrix breakdown (e.g., matrix metalloproteinases [MMPs]) may also be occurring within keloids.
  • MMPs matrix metalloproteinases
  • a keloid is a dense and sharply defined nodular growth of myofibroblasts and collagen with a whorl-like arrangement resembling hypertrophic scar. Centrally, thick hyalinized bundles of collagen are present and distinguish keloids from hypertrophic scars. There is a paucity of elastic tissue, just as in a scar. By pressure, the tumor causes thinning of the normal papillary dermis and atrophy of adjacent appendages, which it pushes aside. Mucopolysaccharides are increased, and often there are numerous mast cells.
  • TGFj-b Transforming growth factor
  • triamcinolone acetonide-induced decreases in cellular proliferation and collagen production are associated with a statistically significant decrease in the level of TGF-bI in both normal and keloid fibroblast cell lines.
  • Other approaches to treatment include flashlamp pulsed dye laser treatment, which is also associated with reduced expression of TGF-b!.
  • Cryosurgery including contact, intralesional needle cryoprobe, and spray cryosurgery
  • intralesional 5-FU intralesional etanercept
  • calcium channel-blockers have some demonstrated efficacy in the treatment of keloids.
  • Proteus syndrome refers to a rare and sporadic disorder characterized by postnatal overgrowth of multiple tissues. This overgrowth may involve the skin and subcutis, connective tissues, central nervous system, and viscera. The involvement characteristically occurs in a patchy (mosaic) and asymmetric pattern. Cutaneous findings are present in approximately 40 percent of neonates and include capillary, lymphatic, or venous malformations, epidermal nevi, connective tissue nevi, lipomas, and cafe au lait macules. The vascular malformations are usually extensive, covering a large portion of the body, and may be associated with visceral vascular malformations. Overgrowth is evident at birth in approximately 20 percent of cases and is asymmetric, disproportionate, and progressive. It may involve many tissues including bone, cartilage, muscle, and connective tissue.
  • Proteus syndrome The etiology of Proteus syndrome is thought to be due to mutations in the AKT1 gene, although there are some reports of a potential association with mutations in the tumor suppressor gene PTEN.
  • Cutaneous manifestations of Proteus syndrome include connective tissue hamartomas, which primarily involve the palms and soles, resulting in cerebriform hyperplasia. Lipomas and extensive fatty hyperplasia may be found in the subcutaneous tissues as well as more diffusely, at times involving body cavities, muscles, and limbs, and regional absence of fat may also occur. Epidermal nevi are common. A variety of cutaneous and subcutaneous vascular malformations may occur, including capillary, venous, and lymphatic malformations. Patchy hypoplasia of the dermis may occur, resulting in prominent cutaneous venous structures.
  • PTEN Hamartoma Tumor Syndromes - As used herein,“PTEN hamartoma tumor syndromes” (PHTS) refers to a group of familial syndromes, which includes Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS). Germline mutations in the phosphatase and tensin homolog ( PTEN) gene have been described in a variety of rare syndromes with different clinical presentations that are collectively known as PTEN hamartoma tumor syndromes. The defining clinical feature of PHTS is the presence of hamartomatous tumors, which are disorganized growths of native cells in native tissues. PHTS is inherited in an autosomal dominant fashion.
  • Cowden syndrome is associated with a high risk for the development of cutaneous hamartomas and internal malignancies such as breast, thyroid and endometrial carcinoma.
  • BRRS is an autosomal dominant disorder characterized by macrocephaly, developmental delay, and penile lentigines.
  • associated vascular malformations are frequently described and usually consist of high flow, intramuscular vascular anomalies associated with increased adipose tissue. These vascular malformations have been found to be quite specific to PTEN hamartoma tumor syndromes and should prompt investigation, workup and continued monitoring for early-onset malignancies in suspected cases.
  • Cowden Syndrome As used herein,“Cowden syndrome” (also known as Cowden disease or multiple hamartoma syndrome) is the best-described phenotype within PHTS. Besides multiple hamartomas in a variety of tissues, patients have characteristic dermatologic manifestations such as trichilemmomas, oral fibromas, and punctate palmoplantar keratoses, and an increased risk of breast, endometrial, thyroid, kidney and colorectal cancers. The range of clinical manifestations of Cowden syndrome includes hamartomatous tumors in multiple organ systems, both mucocutaneous and extracutaneous, and an increased risk for malignancy (including second malignant neoplasms.
  • Trichilemmomas are hamartomatous tumors of the outer root sheath of the hair follicle or other skin appendages that occur on the face and neck of patients with Cowden syndrome. Trichilemmoma is a clinically significant sign of Cowden syndrome when seen in multiplicity (three or more).
  • trichilemmomas are indistinguishable from trichoepitheliomas and other benign follicular tumors affecting the pilosebaceous unit, including fibrofolliculomas and trichodiscomas (which are characteristic lesions of Birt-Hogg-Dube syndrome).
  • Bannayan-Riley-Ruvalcaba Syndrome As used herein,“Bannayan-Riley-Ruvalcaba syndrome” (BRRS, previously referred to as Ruvalcaba-Myhre syndrome, Ruvalcaba-Myhre- Smith syndrome, Riley-Smith syndrome, Bannayan syndrome, or Bannayan-Zonana syndrome) is a rare autosomal dominant disorder that is caused by germline phosphatase and tensin homolog ( PTEN) mutations. RTEN mutations are present in 55 to 60 percent of patients with a clinical diagnosis. Clinical manifestations arise early in childhood, one aspect that can be different from Cowden syndrome. Evaluation is often started in the first few years of life, with a reported median age of diagnosis as young as five years.
  • clinical findings include macrocephaly (at least two standard deviations above the mean), penile lentigines (a very characteristic marker of the disease), GI tract hamartomatous polyps, lipomas, vascular anomalies including arteriovenous shunts and fistulae, intramuscular lesions with a mixture of adipose tissue, fibrous tissue, and abnormal vessels (labeled a PTEN hamartoma of soft tissue, Hashimoto thyroiditis and other thyroid disorders including thyroid cancer, mild-to-severe developmental delay or deficiency, proximal muscle myopathy, high palate, joint hypermobility, and eye abnormalities such as downslanting palpebral fissures, strabismus, and amblyopia.
  • Keratoderma refers to any of a diverse group of hereditary and acquired disorders characterized by hyperkeratosis of the skin on the palms and soles (palmoplantar keratodermas (PPKs)).
  • Unna-Thost type non-epidermolytic PPK
  • Vomer type epidermolytic PPK
  • Meleda type Mai de Meleda
  • Greither type transgrediens and progrediens PPK
  • Gamborg-Nielsen (Norrbotten) type sbert type
  • Vohwinkel syndrome mutilating PPK
  • PPK with sensorineural deafness due to mitochondrial or GJB2 gene defect Bart-Pumphrey syndrome: knuckle pads, leukonychia, and sensorineural deafness
  • Huriez syndrome PPK with scleroatrophy
  • hidrotic ectodermal dysplasia Clouston syndrome
  • Olmsted syndrome mutilating PPK with periorificial plaques
  • Papillon-Lefevre syndrome PPK with periodontitis
  • Haim-Munk syndrome PPK with periodon
  • Richner-Hanhart syndrome oculocutaneous tyrosinemia
  • Carvajal syndrome striate PPK with woolly hair and dilated cardiomyopathy
  • focal palmoplantar and gingival keratosis punctate palmoplantar keratoderma: keratosis punctata palmaris et plantaris, Buschke- Fischer-Brauer type; acrokeratoelastoidosis; focal acral hyperkeratosis; porokeratosis punctata palmaris et plantaris; keratoderma climactericum; spiny keratoderma; keratoderma associated with hypothyroidism/myxedema; keratoderma associated with cancer; aquagenic PPK; drug-induced keratoderma (e.g.
  • keratitis-ichthyosis-deafness (KID) syndrome keratitis-ichthyosis-deafness (KID) syndrome; hystrix-like ichthyosis-deafness (HID) syndrome; erythrokeratodermia variabilis; progressive symmetric erythrokeratoderma; epidermolytic ichthyosis (bullous congenital ichthyosiform erythroderma); ichthyosis hystrix Curth-Macklin; congenital ichthyosiform erythroderma; lamellar ichthyosis; harlequin ichthyosis; Sjogren-Larsson syndrome; Refsum syndrome; CEDNIK (cerebral c/ysgenesis, neuropathy, ichthyosis and keratoderma) syndrome;
  • MEDNIK mental retardation, enteropathy, c/eafness, neuropathy, ichthyosis and keratoderma
  • KLICK syndrome Keratosis /inearis with ichthyosis congenita and sclerosing keratoderma
  • Netherton syndrome rarely
  • ectodermal dysplasia with skin fragility acantholytic ectodermal dysplasia
  • Schopf-Schulz-Passarge syndrome PPK with hidrocystomas, hypodontia and hypotrichosis; odonto-onycho-dermal dysplasia; ectodermal dysplasia-ectrodactyly-clefting (EEC) syndrome; cleft lip/palate ectodermal dysplasia; oculo-dento-digital dysplasia; Naegeli-Franceschetti-Jadassohn syndrome, dermatopathia pigmentosa
  • Acanthosis Nigricans - “acanthosis nigricans” refers to a skin condition characterized by hyperpigmentation and velvet-textured plaques, which are symmetrically distributed.
  • the regions affected may be the face, neck, axillae, external genitals, groin, inner aspects of the thighs, flexor and extensor surface of the elbows and knees, dorsal joints of the hands, umbilicus, and anus.
  • lesions can be found on the areolae, conjunctiva, lips, and buccal mucosa, and around the umbilicus. Rarely, the involvement may be almost universal.
  • the color of the patches is grayish, brownish, or black.
  • the palms or soles may show thickening of the palmar skin with exaggeration of the dermatoglyphs. In severe cases a rugose hypertrophy occurs and can be a sign of malignancy. Small, papillomatous, nonpigmented lesions and pigmented macules may occasionally be found in the mucous membranes of the mouth, pharynx, and vagina. Acrochordons are a frequent accompaniment in the axillae and groin. There is a clear predisposition for certain racial groups to manifest acanthosis nigricans, with Native Americans most commonly affected, followed by African Americans and Hispanics, all above the rates in Caucasians.
  • IGFR1 insulin-like growth factor receptor- 1
  • FGFR fibroblast growth factor receptor
  • EGFR epidermal growth factor receptor
  • mutations in certain FGFRs may contribute to acanthosis nigricans through the promotion of keratinocyte proliferation and survival.
  • Activating mutations in FGFR3 have been linked to several inherited syndromes that present with acanthosis nigricans, including Crouzon syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), thanatophoric dwarfism, and hypochondroplasia.
  • Transforming growth factor (TGF)-alpha a cytokine that may exert proliferative effects via activation of EGFR, may also contribute to the development of malignancy- associated acanthosis nigricans.
  • TGF Transforming growth factor
  • Hyperkeratosis and epidermal papillomatosis are the major pathologic features, and acanthosis is relatively mild.
  • the hyperkeratosis is primarily responsible for the clinical finding of cutaneous hyperpigmentation; however, increased melanin in the basal layer of the epidermis also is sometimes detected.
  • the dermis may demonstrate a mild infiltrate with lymphocytes, plasma cells and, occasionally, a few neutrophils. However, inflammation is not a prominent feature.
  • Biopsies of mucosal lesions exhibit mild parakeratosis with epidermal hyperplasia and papillomatosis.
  • Treatment of the underlying cause is the preferred method of management, and obesity-related, drug- induced, and malignancy-associated acanthosis nigricans appear to frequently respond well to this intervention.
  • the likelihood for clinically significant improvement in acanthosis nigricans following the treatment of insulin resistant states is less certain.
  • topical therapies that normalize epidermal proliferation, such as topical retinoids and topical vitamin D analogs, have been tried. Systemic retinoids have also been utilized for this indication, but are not indicated for the treatment of most patients.
  • Birt-Hogg-Dube syndrome refers to an autosomal dominant condition first described in 1977, characterized by benign skin hamartomas, most commonly located on the head and neck; pulmonary cysts and spontaneous pneumothorax; and an increased risk of renal cancer.
  • BHD syndrome is caused by germline mutations in the folliculin gene ( FLCN ), which encodes the protein folliculin, a putative tumor suppressor gene whose function is still under investigation.
  • the phenotype of Birt-Hogg-Dube (BHD) syndrome is highly heterogeneous within families and between families sharing the same folliculin ( FLCN) mutation.
  • Fibrofolliculoma a benign hamartoma of the hair follicle, is the hallmark skin finding of Birt-Hogg-Dube (BHD) syndrome. Fibrofolliculomas are typically the earliest and most frequent manifestation of BHD syndrome. They begin to appear in the third decade of life in approximately 90 percent of patients and present as round, white-gray papules 1 to 4 mm in size, some of which show a dell in the center corresponding to the follicular opening. Lesions as large as 8 mm and cystic or comedonal lesions may also occur.
  • BHD Birt-Hogg-Dube
  • the midface (cheeks, nose) is most densely affected, and the papules are also often most prominent at this location, particularly in fair-skinned individuals with a rosaceiform complexion. Lesions may develop anywhere on the head/neck, including the posterior ears. Isolated papules on the neck may be difficult to differentiate from acrochordons (skin tags) or small seborrheic keratoses. Affected patients will continue to slowly accumulate new lesions and experience enlargement of pre-existing lesions throughout life. However, some patients have only a small number of lesions by late adulthood, whereas others may develop hundreds, at times near confluent, in the head/neck area.
  • fibrofolliculomas include trichodiscomas and acrochordons. Trichodiscomas are clinically indistinguishable from fibrofolliculomas and may represent a histologic variant of the same tumor. Acrochordons (skin tags) are common in the general population, and their presence or absence is not helpful in making/excluding a diagnosis of BHD syndrome.
  • Angiofibromas also known as fibrous papules
  • fibrous papules may occasionally be seen in the setting of BHD syndrome but are also common in the general population.
  • Fibrofolliculomas and trichodiscomas are benign lesions that usually do not require treatment. However, some patients with numerous facial lesions may seek treatment because of cosmetic concerns. Destructive therapies, including shave removal, electrodessication with or without curettage, and carbon dioxide (CO2) or erbiurmyttrium aluminum garnet (EnYAG) laser ablation, have been used in a few patients with good results, although recurrence is commonplace. In a randomized, split- face trial including 19 patients, topical rapamycin (sirolimus) 0.1% oral solution did not result in reduction in size or number of fibrofolliculoma lesions compared with placebo.
  • rapamycin sirolimus
  • Cylindromas - Yet other skin lesions described in BHD syndrome include cylindromas (also known as turban tumors). These are benign neoplasms of either eccrine or apocrine origin, characterized by firm, rubbery, pink to bluish plaques and nodules.
  • Cylindromas may occur singly or in multiples, and occasionally coalesce to result in large mosaic tumors. Multiple lesions may occur as part of the autosomal dominant Brooke-Spiegler syndrome (with multiple trichoepitheliomas and occasionally other appendageal tumors. This disease has been mapped to 16ql2— 13, and mutations in the CYLD gene have been identified in families with this disorder. Cylindromas are almost invariably benign, although malignant transformation has been rarely reported. Current treatment consists of surgical excision, although CO2 laser surgery has also been demonstrated useful.
  • Brooke-Spiegler Syndrome refers to a rare condition with a predisposition to develop cutaneous adnexal neoplasms, especially cylindromas, trichoepitheliomas and spiradenomas. Malignant transformation of cylindromas is rare. In such cases usually cylindrocarcinomas develop within these lesions. Brooke-Spiegler syndrome is caused by mutations in the CYLD gene.
  • epidermal nevi can be divided into non-organoid (keratinocytic) nevi and organoid epidermal nevi, such as nevus sebaceous or follicular nevi.
  • FGFR3 fibroblast growth factor receptor 3
  • Keratinocytic epidermal nevi may be slightly or darkly pigmented and unilateral or bilateral in distribution. They often favor the extremities, although they may occur anywhere on the cutaneous surface.
  • Epidermal nevi are usually distributed in a mosaic pattern of alternating stripes of involved and uninvolved skin. This pattern is termed“Blaschko’s lines” and occurs as a result of migration of skin cells during embryogenesis. Disorders that occur along Blaschko’s lines usually reveal a linear pattern on the extremities and a wavy or arcuate pattern on the trunk. Although a single epidermal nevus is most common, multiple lesions may be present, sometimes in association with the“epidermal nevus syndrome” (see below). The localized form is often present at birth and presents as a tan to brown, velvety or verrucous (warty) papule or plaque.
  • epidermal nevus There may be a single lesion or multiple lesions, and a linear configuration is common.
  • epidermal nevus has been termed the acanthosis nigricans form of epidermal nevi, and it is characterized by a clinical and histologic resemblance to acanthosis nigricans.
  • Epidermal nevi may reveal a variety of histologic features. Importantly, those that reveal“epidermolytic hyperkeratosis,” a distinct pattern of clumping of keratin filaments in the suprabasal cells of the epidermis, imply a mosaic disorder of keratin genes. These patients, especially when skin involvement is extensive, may transmit these mutations to offspring, resulting in a more widespread ichthyosiform condition termed“epidermolytic ichthyosis” (formerly“bullous congenital ichthyosiform erythroderma,” and“epidermolytic hyperkeratosis”). These epidermal nevi may be clinically indistinguishable from other epidermal nevi.
  • Epidermal nevi are challenging to treat, given the observation that most superficial destructive therapies are followed by recurrence of the lesion(s). These superficial therapies have included cryotherapy with liquid nitrogen, dermabrasion, electrodesiccation, and laser ablation. CO2 laser therapy may offer excellent results, but response to therapy is unpredictable. Staged CO2 laser ablation has been used successfully, both with and without preceding surgical debulking. Topical therapies used with variable success include retinoids, 5-fluorouracil, steroids, and podophyllin, among others. Full-thickness surgical excision or deeper destructive procedures (such as deep dermabrasion) appear effective at removing these hamartomas, but are generally limited to smaller, more localized lesions. Since these lesions may continue to extend during childhood, surgical intervention is usually delayed until the full extent of the process is determined.
  • IVSEN Inflammatory linear verrucous epidermal nevus
  • Nevus sebaceous of Jadassohn is a common congenital lesion that occurs mainly on the face and scalp. These lesions are usually solitary, and present as a well-circumscribed, hairless plaque. A developmental defect, they are generally present at birth, but may first be noted during early childhood and rarely in adult life. Although rare familial forms have been reported, these hamartomas tend to be sporadic. Multiple nevi sebaceous may occur in association with cerebral, ocular, and skeletal abnormalities as part of the epidermal nevus syndrome. This association has been termed Schimmelpenning syndrome.
  • An epidermal nevus is a congenital overgrowth of epidermal cells that is often due to a mosaic mutation, sometimes involving mutations in fibroblast growth factor receptor 3 (FGFR3).
  • the mTOR complex is known to negatively regulate FGFR3.
  • topical mTOR inhibitor such as rapamycin would be effective in treating some epidermal nevi due to this direct pathway involvement and the favorable results of studies disclosed in the Examples herein.
  • a“cutaneous vascular condition” refers to a skin condition characterized by abnormal or undesirable proliferation of principally vascular structures or vascular tissue in skin.
  • the skin condition characterized by abnormal or undesirable proliferation of principally vascular structures or vascular tissue in skin can be a cutaneous manifestation of a multisystemic or more general condition that is not confined to skin.
  • any cutaneous proliferative condition as defined herein is considered to be, or can be considered to be, a cutaneous vascular condition
  • such cutaneous proliferative condition is to be understood also to be included among cutaneous vascular conditions in accordance with the invention.
  • Cutaneous vascular conditions include, without limitation, PIK3CA-related overgrowth spectrum (PROS), venolymphatic malformations, acne, acne rosacea (including rhinophyma), periorifacial dermatitis (also known as perioral dermatitis), fibrous papules, acne vulgaris, cutaneous capillary malformation-arteriovenous malformation (CM-AVM) syndrome, and RASopathies, including neurofibromas.
  • PROS PIK3CA-related overgrowth spectrum
  • venolymphatic malformations include, without limitation, venolymphatic malformations, acne, acne rosacea (including rhinophyma), periorifacial dermatitis (also known as perioral dermatitis), fibrous papules, acne vulgaris, cutaneous capillary malformation-arteriovenous malformation (CM-AVM) syndrome, and RASopathies, including neurofibromas.
  • the cutaneous vascular condition is venolymphatic malformations.
  • cutaneous vascular conditions exclude any one or more of facial angiofibromas in tuberous sclerosis, microcystic lymphatic malformations, and port wine stains.
  • Rapamycin has been reported to be effective in the treatment of several vascular conditions, namely port wine stains (PWS) in combination with laser, facial angiofibromas either alone or in combination with pulsed dye laser treatments, and other cutaneous features of Tuberous Sclerosis Complex. Animal studies and preliminary studies on normal human skin have demonstrated the effectiveness of rapamycin in inhibiting
  • PDL pulsed dye laser
  • mTOR inhibitors have shown promise as a systemic treatment of complex vascular malformations in children, including venolymphatic malformations. Overexpression of mTOR has been found in some vascular malformations.
  • the phosphoinositide-3-kinase (PI3K)/Akt pathway which is implicated in some vascular anomalies, is an upstream regulator/inducer of the mTOR complex. Therefore, the mechanism of sirolimus in treating vascular malformations may be by preventing the downstream effects of PIK3CA/AKT overexpression.
  • VEGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • lymphangiogenesis a key regulator in angiogenesis and lymphangiogenesis, potentially both stimulates the mTOR pathway and downstream appears to be effected by mTOR, and mTOR inhibitors have been shown to decrease both the secretion of VEGF and the sensitivity of its receptors.
  • the components of the PI3K/AKT/mTOR pathway are known to interact with other pathways, including Ras/MAPK (Ras/mitogen-activated protein kinases) pathway.
  • Ras/MAPK Ras/mitogen-activated protein kinases
  • CM-AVM Capillary malformation-arteriovenous malformation
  • RASopathies syndromes and diseases due to mutations in the RAS pathway
  • mTOR inhibitor systemic or topical
  • Such conditions include but are not limited to autoimmune lymphoproliferative syndrome, cardiofaciocutaneous syndrome, hereditary gingival fibromatosis,
  • neurofibromatosis type 1 Noonan syndrome, Costello syndrome, Legius syndrome, and Noonan syndrome with multiple lentigines. Additionally, the cutaneous lesions that characterize these conditions, including but not limited to neurofibromas, are similarly expected by the inventor to respond to treatment with systemic or topical mTOR inhibitors.
  • PIK3CA-Related Overgrowth Spectrum - As used herein,“PIK3CA-related overgrowth spectrum” (PROS) refers to certain syndromes associated with various vascular anomalies. Somatic PIK3CA mutations are the most common cause of isolated lymphatic malformations and disorders in which lymphatic malformation is a component feature. Broadly speaking, these syndromes can be classified as syndromes associated with capillary malformations and syndromes associated with venous malformations.
  • Syndromes associated with capillary malformations include Sturge-Weber syndrome, macrocephaly capillary malformation syndrome (megalencephaly capillary malformation polymicrogyria syndrome), Beckwith-Wiedemann syndrome, Nova syndrome, and phakomatosis pigmentovascularis (PPV).
  • Syndromes associated with venous malformations include venous malformations cutaneous and mucosal (VMCM), glomuvenous malformations, blue rubber bleb nevus syndrome (Bean syndrome), Maffucci syndrome, cutis marmorata telangiectatica congenita, and capillary malformation-arteriovenous malformation.
  • Gain- of- function mutations in PIK3CA lead to the activation of protein kinase B (AKT) and, ultimately, mammalian target of rapamycin (mTOR), with resultant cell proliferation and angiogenesis.
  • Similar mutations have been discovered in entities such as congenital lipomatous overgrowth with vascular malformations, epidermal nevi, and skeletal anomalies (CLOVES) syndrome, fibro-adipose vascular anomaly (FAVA), and macrocephaly-capillary malformation (M-CM, MCAP) syndrome.
  • Sturge-Weber Syndrome The classic triad in Sturge-Weber syndrome (SWS) includes the association of a facial port-wine stain (PWS), invariably involving VI (although it may be more extensive), ipsilateral eye abnormalities (choroidal vascular anomalies, increased ocular pressure, buphthalmos, and glaucoma), and leptomeningeal and brain abnormalities (leptomeningeal vascular malformation, calcifications, cerebral atrophy, enlarged choroid plexus, and developmental venous anomalies in the brain).
  • PWS facial port-wine stain
  • VI ipsilateral eye abnormalities
  • leptomeningeal and brain abnormalities leptomeningeal vascular malformation, calcifications, cerebral atrophy, enlarged choroid plexus, and developmental venous anomalies in the brain.
  • VI, V2, and V3 refer to areas served by the upper, middle, and lower facial sensory branches of the trigeminal nerve (i.e., cranial nerve V), respectively.
  • the risk of SWS with VI PWS alone is variably reported but is approximately 10%. The risk increases to >25% with either bilateral VI or concurrent V 1 , V2, and V3 involvement. Patients with V2 or V3 PWS alone without involvement of the V 1 skin are not at risk for SWS.
  • individual anatomic variations in the distribution of V 1 and V2 at the internal or external canthus of the eye may pose difficulties in determining whether a port- wine stain involves V 1 , with its associated risk of SWS.
  • the possibility of SWS should be considered in any infant with a PWS that includes the VI distribution.
  • SWS can cause significant medical and ophthalmologic problems. Consequences of intracranial vascular anomalies include seizures, headaches (including migraines), spastic hemiparesis, visual field defects, cognitive impairment and behavioral disorders including attention deficit disorder. Transient ischemic attacks and strokes may also occur in some patients. An increased prevalence of growth hormone deficiency and hypothyroidism is described in patients with SWS, so at-risk individuals need to be assessed for these potential complications. Potential visual loss via acute or chronic glaucoma requires ongoing ophthalmologic follow-up throughout a patient’s lifetime. Even an individual who has a VI PWS without CNS findings should have periodic ophthalmologic evaluations throughout their lifetime.
  • the pathogenesis of SWS has recently been attributed to somatic activating mutations in GNAQ, the gene encoding guanine nucleotide -binding protein G(q) subunit alpha.
  • the three mesectodermal tissues involved (the nasofrontal skin known as VI skin, the ocular choroid, and the leptomeninges) have a common origin in the anterior neural primordium, and a somatic mutation arising during development has been hypothesized.
  • Neuroimaging consisting of MRJ with gadolinium enhancement may be helpful in making an early diagnosis, but can be normal in some cases. Early subtle changes on standard MRI can include an enlarged choroid plexus or a pattern of local accelerated myelination.
  • Typical neuroimaging changes include visualization of the pial vascular malformation, cerebral atrophy, and calcifications of the leptomeninges, the abnormal cortex and the underlying white matter.
  • Newer MRI modalities such as susceptibility- weighted imaging may prove useful in detecting abnormalities earlier in life.
  • the first seizures in SWS occur before 2 years of age but may arise later in life.
  • the progressive nature of SWS has been demonstrated using functional neuroimaging tools, with hyperperfusion noted prior to the development of seizures, followed by hypoperfusion with decreased glucose utilization after the onset of seizures.
  • Macrocephaly Capillary Malformation Syndrome Macrocephaly capillary malformation syndrome (MCM/MCAP) was formerly known as macrocephaly CMTC.
  • MCM/MCAP is associated with megalencephaly, developmental delay, brain and body asymmetry, capillary malformations, digital anomalies (syndactyly, polydactyly), and brain malformations; characteristically, polymicrogyria. Other features include seizures, developmental delay, hydrocephalus, and joint laxity. Recently, the genetic basis for this condition has been identified. Affected individuals have been reported to harbor mutations in the AKT3, PIK3CA or PIK3R2 genes. MCM/MCAP is a heterogeneous overgrowth syndrome, and most commonly patients present with macrocephaly and cutaneous capillary malformations. The associated capillary stain is most commonly located on the central face (philtrum and glabella) but can be seen on any area of the body.
  • Beckwith- Wiedemann Syndrome - Beckwith- Wiedemann syndrome is a pediatric overgrowth disorder that carries an increased risk for malignancy, specifically Wilms tumor. BWS can present antenatally with visceromegaly on prenatal
  • ultrasonography It is associated with persistent nevus simplex or capillary malformation of the mid-forehead.
  • Other findings include overgrowth of tissues and organs, macroglossia, and abdominal wall defects, usually omphalocele. High birthweight, hemihypertrophy, and neonatal hypoglycemia are also reported. Intelligence is usually not impaired.
  • Nova Syndrome - Nova syndrome is a familial disorder in which a congenital glabellar capillary stain occurs in association with neurologic malformations, including Dandy-Walker malformation, hydrocephalus, cerebellar vermis agenesis, and mega cistema magna.
  • Phakomatosis pigmentovascularis As used herein,“phakomatosis
  • pigmentovascularis refers to the association of cutaneous pigmentary and vascular anomalies. Five types with two subtypes per group are classically described. Capillary malformations are described in types I-IV and cutis marmorata telangiectatica congenita in type V. The pigmentary anomalies include blue-gray macules/patches (dermal melanocytosis), nevus spilus and epidermal nevi which are darkly pigmented. Nevus anemicus is also reported. PPV has been described in association with other vascular anomalies including Klippel-Trenaunay syndrome and Sturge- Weber syndrome.
  • VMCM Venous Malformations Cutaneous and Mucosal
  • Glomuvenous Malformations Familial glomuvenous malformations are usually inherited in an autosomal dominant manner, but can also be sporadic. Mutations in the glomulin gene have been identified in affected patients. GVM often resemble VM clinically. They can be small or large/segmental in their appearance. They are bluish to purple, cobblestoned in appearance and often painful on palpation. There is great heterogeneity among affected family members, which suggests that a single mutation in the glomulin gene is not enough to produce the lesion, thus as in VMCM, a second post- zygotic mutation in the unaffected allele is required for the lesion to develop.
  • BBRNS blue rubber bleb nevus syndrome
  • VMs typically small black-blue papules and skin-colored subcutaneous nodules that often involve the palms and soles. GI bleeding is a frequent clinical feature of this syndrome.
  • Enchondromas are benign cartilage-forming tumors within the medullary cavity of the bone. These tumors are identical to those present in another form of multiple enchondromatosis, Ollier disease. They involve both the metaphyses and the diaphyses, and may cause bony distortion, fragility, and shortening of an affected limb. The hands and feet are involved in 90% of patients. Cranial
  • enchondromas result in severe neuro-ophthalmologic consequences. Over time, enchondromas may develop malignant transformation. Somatic mosaic 1DH1 and IDH2 mutations are associated with the lesions in both Ollier disease and MS.
  • Cutis Marmorata Telangiectatica Congenita refers to a form of vascular malformation with a distinctive reticulated pattern. Most cases are sporadic. A female predominance is reported in some cases series, while others show no difference in incidence among genders. CMTC can be confined to a small area, have a regional distribution, or more diffuse skin involvement. At birth, a reticulated purple network is noted. The skin is streaked with linear and patchy vascular lesions intermingled with telangiectasia.
  • CMTC may be associated with port-wine stains, which can become more apparent with maturity as the reticulate lesions fade.
  • CMTC may improve with age, but rarely disappears completely with areas of atrophy often persisting. Ulcerations may continue to arise during infancy and childhood, particularly in areas overlying the joints, resulting in scaly areas of scarring.
  • KTS Klippel-Trenaunay syndrome
  • Parkes-Weber Syndrome refers to a condition characterized by a large capillary malformation on an extremity, soft tissue and bone hypertrophy of the affected limb, and multiple, microscopic, fast- flow arteriovenous shunts.
  • the capillary malformation of Parkes-Weber syndrome is indistinguishable from the port wine stain seen in KTS. Ultrasonography, MRJ, and magnetic resonance arteriography are helpful in differentiating Parkes-Weber syndrome from KTS.
  • CLOVES Syndrome refers to congenital /ipomatous overgrowth, vascular malformations, epidermal nevi and skeletal
  • anomalies/scoliosis is a very rare congenital overgrowth syndrome resulting from post zygotic activating mutations in the PIK3CA gene.
  • Macrocephaly- capillary malformation (M-CM) syndrome refers to a genetic syndrome characterized by an enlarged head circumference and patchy, reticular capillary malformations. It is caused by mutations in the PIK3CA gene, leading to gain of function and activation of the PI3K-AKT pathway, which is involved in cell growth, proliferation, survival, and apoptosis.
  • the capillary malformations are usually reticulated and widespread on the trunk and extremities. Cardiac abnormalities including aortic coarctation have also been described.
  • Neuroimaging findings include white matter abnormalities, ventriculomegaly, cerebral asymmetry, cortical dysplasia, polymicrogyria-like changes, and cerebellar tonsil herniation.
  • acne rosacea is a vascular proliferative condition that the inventor expects will respond to treatment with a topical mTOR inhibitor.
  • Acne rosacea also known simply as“rosacea,” is a common chronic vascular inflammatory condition characterized by erythema, telangiectasia, papules and pustules, and occasionally soft tissue hypertrophy (including rhinophyma), typically located on the face.
  • the pathophysiology of rosacea is thought to be multifactorial; however, this common condition is known to present with clinical erythema and vascular manifestations such as telangiectasias.
  • angiogenesis itself has been reported to play an important role in the pathogenesis of rosacea.
  • Currently available treatments are numerous but often suboptimal.
  • Basic science and other research studies have demonstrated the effectiveness of mTOR inhibitors in decreasing angiogenesis in other models.
  • topical mTOR inhibitors such as topical rapamycin will be effective in the treatment of acne rosacea.
  • Periorificial Dermatitis - Periorificial dermatitis also known as perioral dermatitis, is another common acneiform condition that presents in children and young adults.
  • Periorificial dermatitis is often considered a juvenile form of acne rosacea as they share overlapping histologic features. Hence, the inventor also believes topical mTOR inhibitors such as topical rapamycin will be effective in the treatment of periorificial dermatitis.
  • Fibrous Papules - Fibrous papules of the nose are skin-colored to white, firm, 1 to 3 mm papules that usually occur singly or in small numbers, often on the nose or midface, in late adulthood.
  • these lesions resemble angiofibromas and show a normal epidermis, sometimes with an increased number of clear cells overlying the lesion, increased dermal collagen with ectatic blood vessels, and increased dermal cellularity composed of mono- and multinucleated cells with a histiocyte-like appearance.
  • topical mTOR inhibitors such as topical rapamycin will be effective in the treatment of fibrous papules.
  • CM-AVM Capillary Malformation- Arteriovenous Malformation
  • CM-AVM capillary malformation-arteriovenous malformation
  • CM-AVM chronic sarcoma
  • RASA1 Reactive Access to Session Initiation Syndrome
  • CM-AVM CM-AVM is inherited as an autosomal dominant trait, with wide expressivity. Some affected family members may have symptomatic AVMs, whereas others exhibit only small, pink patches, however the true incidence of underlying AVM is not fully understood because not all individuals have undergone complete evaluation. In the families that have been evaluated, approximately two-thirds of individuals will have the AVM located in the soft tissue and one-third in the central nervous system. In many patients, the AVM will underlie the largest CM.
  • Parkes-Weber syndrome (see below) is one of the ways CM-AVM will present and may do so in the neonatal period with an enlarged limb, overlying CM and an underlying fast- flow AVM or AVF, or vein of Galen malformation which can lead to cardiac compromise.
  • An aspect of the invention is a method of treating a cutaneous proliferative condition, comprising topically administering to an affected area of a subject in need thereof a therapeutically effective amount of a mammalian target of rapamycin (mTOR) inhibitor, thereby treating the condition.
  • mTOR mammalian target of rapamycin
  • a“cutaneous proliferative condition” refers to refers to a skin condition characterized by abnormal or undesirable proliferation of principally non- vascular structures or non- vascular tissue in skin.
  • “skin” refers to any or all of epidermis, dermis, and hypodermis, and appendages, glands, and blood and lymphatic vessels therein. See, for example, Bloom and Fawcett, A Textbook of Flistology, 10* Ed., W.B. Saunders, Philadelphia, 1975.
  • any cutaneous vascular condition as defined herein is considered to be, or can be considered to be, a cutaneous proliferative condition, such cutaneous vascular condition is to be understood also to be included among cutaneous proliferative conditions in accordance with the invention.
  • the cutaneous proliferative condition excludes any one or more of trichoepithelioma and familial multiple discoid fibroma.
  • Cutaneous proliferative conditions include, without limitation, histiocytosis, scars, hypertrophic or keloidal scars, Proteus syndrome, PTEN hamartoma tumor syndromes, Cowden syndrome, Babbayan-Riley-Ruvalcaba syndrome, cutaneous malignancies and tumors associated with PI3K/AKT/mTOR mutations, keratoderma, acanthosis nigricans, Birt-Hogg-Dube syndrome, Brooke- Spiegler syndrome, cylindromas, and epidermal nevi.
  • the cutaneous proliferative condition is histiocytosis.
  • the cutaneous proliferative condition is scars.
  • the cutaneous proliferative condition is hypertrophic scars.
  • the cutaneous proliferative condition is keloids.
  • the cutaneous proliferative condition is Proteus syndrome.
  • the cutaneous proliferative condition is PTEN hamartoma tumor syndromes.
  • the cutaneous proliferative condition is Cowden syndrome.
  • the cutaneous proliferative condition is Babbayan-Riley- Ruvalcaba syndrome.
  • the cutaneous proliferative condition is cutaneous malignancies and tumors associated with PI3K/AKT/mTOR mutations.
  • the cutaneous proliferative condition is keratoderma.
  • the cutaneous proliferative condition is acanthosis nigricans.
  • the cutaneous proliferative condition is Birt-Hogg-Dube syndrome.
  • the cutaneous proliferative condition is Brooke- Spiegler syndrome.
  • the cutaneous proliferative condition is cylindroma.
  • the cutaneous proliferative condition is epidermal nevi.
  • the cutaneous vascular condition excludes histiocytosis.
  • the cutaneous proliferative condition excludes scars.
  • the cutaneous proliferative condition excludes hypertrophic scars.
  • the cutaneous proliferative condition excludes keloids.
  • the cutaneous proliferative condition excludes Proteus syndrome. In certain embodiments, the cutaneous proliferative condition excludes PTEN hamartoma tumor syndromes.
  • the cutaneous proliferative condition excludes Cowden syndrome.
  • the cutaneous proliferative condition excludes Babbayan- Riley-Ruvalcaba syndrome.
  • the cutaneous proliferative condition excludes cutaneous malignancies and tumors associated with PI3K/AKT/mTOR mutations.
  • the cutaneous proliferative condition excludes keratoderma.
  • the cutaneous proliferative condition excludes acanthosis nigricans.
  • the cutaneous proliferative condition excludes Birt-Hogg- Dube syndrome.
  • the cutaneous proliferative condition excludes Brooke - Spiegler syndrome.
  • the cutaneous proliferative condition excludes cylindroma.
  • the cutaneous proliferative condition excludes epidermal nevi.
  • Histiocytosis includes, without limitation, Langerhans cell histiocytosis and non- Langerhans cell histiocytosis (non-LCH).
  • Langerhans cell histiocytosis includes, without limitation, histiocytosis X, eosinophilic granuloma, Letterer-Siwe disease, Hand-Schuller-Christian syndrome, and Hashimoto-Pritzker syndrome.
  • the histiocytosis is Langerhans cell histiocytosis.
  • the histiocytosis is histiocytosis X.
  • the histiocytosis is eosinophilic granuloma.
  • the histiocytosis is Letterer-Siwe disease.
  • the histiocytosis is Hand-Schuller-Christian syndrome.
  • the histiocytosis is Hashimoto-Pritzker syndrome.
  • the histiocytosis excludes Langerhans cell histiocytosis.
  • the histiocytosis excludes histiocytosis X.
  • the histiocytosis excludes eosinophilic granuloma.
  • the histiocytosis excludes Letterer-Siwe disease. In certain embodiments, the histiocytosis excludes Hand-Schuller-Christian syndrome.
  • the histiocytosis excludes Hashimoto-Pritzker syndrome.
  • Non-Langerhans cell histiocytosis includes, without limitation, benign cephalic histiocytosis (BCH), juvenile xanthogranuloma, xanthoma disseminatum, necrobiotic xanthogranuloma, generalized eruptive histiocytoma, progressive nodular histiocytoma, indeterminate cell histiocytosis, multicentric reticulohistiocytosis, and sinus histiocytosis with massive lymphadenopathy.
  • BCH benign cephalic histiocytosis
  • juvenile xanthogranuloma juvenile xanthogranuloma
  • xanthoma disseminatum necrobiotic xanthogranuloma
  • generalized eruptive histiocytoma progressive nodular histiocytoma
  • indeterminate cell histiocytosis multicentric reticulohistiocyto
  • the histiocytosis is non-Langerhans cell histiocytosis (non-langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhans cell histiocytosis (non-Langerhan
  • the histiocytosis is cephalic histiocytosis (BCH).
  • the histiocytosis is juvenile xanthogranuloma.
  • the histiocytosis is xanthoma disseminatum.
  • the histiocytosis is necrobiotic xanthogranuloma.
  • the histiocytosis is generalized eruptive histiocytoma.
  • the histiocytosis is progressive nodular histiocytoma.
  • the histiocytosis is indeterminate cell histiocytosis.
  • the histiocytosis is multicentric reticulohistiocytosis.
  • the histiocytosis is sinus histiocytosis with massive lymphadenopathy.
  • the histiocytosis excludes non-Langerhans cell histiocytosis (non-LCH).
  • the histiocytosis excludes cephalic histiocytosis (BCH).
  • the histiocytosis excludes juvenile xanthogranuloma.
  • the histiocytosis excludes xanthoma disseminatum.
  • the histiocytosis excludes necrobiotic xanthogranuloma.
  • the histiocytosis excludes generalized eruptive
  • the histiocytosis excludes progressive nodular
  • the histiocytosis excludes indeterminate cell histiocytosis.
  • the histiocytosis excludes multicentric reticulohistiocytosis. In certain embodiments, the histiocytosis excludes sinus histiocytosis with massive lymphadenopathy.
  • topically administering refers to applying to a surface of skin. Such administering can be achieved by any suitable method and means, and it may include rubbing or spreading a pharmaceutically active agent or pharmaceutical composition on the surface of the skin to promote uniformity of distribution and/or enhance absorption into the skin.
  • an“affected area” refers to an area of skin which is clinically involved in the condition to be treated.
  • An affected area can be defined by clinical inspection, with or without benefit of histologic diagnosis (e.g., biopsy).
  • the affected area comprises at least a portion of any one or more of the head, face, and neck.
  • a“subject” refers to a living mammal. In certain embodiments, a subject is a human.
  • the subject is a human less than 18 years of age. In certain embodiments, the subject is a human 1 to less than 6 years of age. In certain embodiments, the subject is a human 6 to less than 10 years of age. In certain embodiments, the subject is a human 10 to less than 14 years of age. In certain embodiments, the subject is a human 14 to less than 18 years of age.
  • the subject is a human at least 18 years of age.
  • an“effective amount” is an amount that is sufficient to achieve a desired biological effect.
  • a“therapeutically effective amount” is an amount that is sufficient to achieve a desired therapeutic effect.
  • “treat” and“treating” refer to reducing and/or ameliorating at least one sign or symptom of a condition of a subject.
  • the reducing can be partial or complete.
  • the mTOR inhibitor is selected from the group consisting of sirolimus and everolimus.
  • the mTOR inhibitor comprises sirolimus.
  • the mTOR inhibitor comprises everolimus.
  • the mTOR inhibitor consists of sirolimus.
  • the mTOR inhibitor consists of everolimus. In certain embodiments, the mTOR inhibitor is provided as a topical formulation comprising 0.01% to 10% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation comprising 0.05% to 5% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation comprising 0.1% to 2% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation consisting of 0.01% to 10% (w/v) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation consisting of 0.05% to 5% (w/v) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation consisting of 0.1% to 2% (w/v) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided in combination with a PI3K inhibitor.
  • dual mTOR '' PI3K inhibitors include without limitation dactolisib, BGT226, SF1126, and PKI- 587.
  • An aspect of the invention is a method of treating a cutaneous vascular condition, comprising topically administering to an affected area of a subject in need thereof a therapeutically effective amount of a mammalian target of rapamycin (mTOR) inhibitor, thereby treating the condition.
  • mTOR mammalian target of rapamycin
  • a“cutaneous vascular condition” refers to a skin condition characterized by abnormal or undesirable proliferation of principally vascular structures or vascular tissue in skin.
  • cutaneous proliferative condition as defined herein is considered to be, or can be considered to be, a cutaneous vascular condition
  • cutaneous proliferative condition is to be understood also to be included among cutaneous vascular conditions in accordance with the invention.
  • cutaneous vascular conditions exclude any one or more of facial angiofibromas in tuberous sclerosis, microcystic lymphatic malformations, and port wine stains.
  • Cutaneous vascular conditions include, without limitation, PIK3CA-related overgrowth spectrum (PROS), venolymphatic malformations, acne, acne rosacea, periorifacial dermatitis (also known as perioral dermatitis), fibrous papules, acne vulgaris, and cutaneous capillary malformation-arteriovenous malformation (CM-AVM) syndrome and other RASopathies.
  • PROS PIK3CA-related overgrowth spectrum
  • venolymphatic malformations include, without limitation, PIK3CA-related overgrowth spectrum (PROS), venolymphatic malformations, acne, acne rosacea, periorifacial dermatitis (also known as perioral dermatitis), fibrous papules, acne vulgaris, and cutaneous capillary malformation-arteriovenous malformation (CM-AVM) syndrome and other RASopathies.
  • CM-AVM cutaneous capillary malformation-arteriovenous malformation
  • the cutaneous vascular condition is PIK3CA-related overgrowth spectrum (PROS).
  • PROS PIK3CA-related overgrowth spectrum
  • the cutaneous vascular condition is venolymphatic malformations.
  • the cutaneous vascular condition is acne.
  • the cutaneous vascular condition is acne rosacea
  • the cutaneous vascular condition is periorifacial dermatitis
  • the cutaneous vascular condition is fibrous papules
  • the cutaneous vascular condition is acne vulgaris
  • the cutaneous vascular condition is cutaneous capillary malformation- arteriovenous malformation (CM-AVM) syndrome.
  • CCM-AVM cutaneous capillary malformation- arteriovenous malformation
  • the cutaneous vascular condition is a RASopathy.
  • the RASopathy is a neurofibroma.
  • the cutaneous vascular condition excludes PIK3CA-related overgrowth spectrum (PROS).
  • PROS PIK3CA-related overgrowth spectrum
  • the cutaneous vascular condition excludes a venolymphatic malformation.
  • the cutaneous vascular condition exludes acne.
  • the cutaneous vascular condition excludes acne rosacea.
  • the cutaneous vascular condition excludes periorifacial dermatitis.
  • the cutaneous vascular condition excludes fibrous papules.
  • the cutaneous vascular condition excludes acne vulgaris.
  • the cutaneous vascular condition excludes cutaneous capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In certain embodiments, the cutaneous vascular condition excludes RASopathy.
  • CCM-AVM cutaneous capillary malformation-arteriovenous malformation
  • the cutaneous vascular condition excludes any one or more of facial angiofibromas in tuberous sclerosis, microcystic lymphatic malformations, and port wine stains.
  • the cutaneous vascular condition excludes facial angiofibromas in tuberous sclerosis.
  • the cutaneous vascular condition excludes microcystic lymphatic malformations.
  • the cutaneous vascular condition excludes port wine stains.
  • the affected area comprises at least a portion any one or more of the head, face, and neck.
  • the mTOR inhibitor is selected from the group consisting of sirolimus and everolimus.
  • the mTOR inhibitor comprises sirolimus.
  • the mTOR inhibitor comprises everolimus.
  • the mTOR inhibitor consists of sirolimus.
  • the mTOR inhibitor consists of everolimus.
  • the mTOR inhibitor is provided as a topical formulation comprising 0.01% to 10% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation comprising 0.05% to 5% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation comprising 0.1% to 2% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation consisting of 0.01% to 10% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided as a topical formulation consisting of 0.05% to 5% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable earner. In certain embodiments, the mTOR inhibitor is provided as a topical formulation consisting of 0.1% to 2% (w/w) of the mTOR inhibitor in a pharmaceutically acceptable carrier.
  • the mTOR inhibitor is provided in combination with a PI3K inhibitor.
  • the subject is a human less than 18 years of age. In certain embodiments, the subject is a human 1 to less than 6 years of age. In certain embodiments, the subject is a human 6 to less than 10 years of age. In certain embodiments, the subject is a human 10 to less thanl4 years of age. In certain embodiments, the subject is a human 14 to less than 18 years of age.
  • the subject is a human at least 18 years of age.
  • mTOR inhibitors are formulated in oral solution or tablet form. Various commercially available mTOR inhibitors are also formulated for intravenous administration. In accordance with certain embodiments of the present invention, mTOR inhibitor is formulated primarily for topical administration. Currently there is no standard or commercially available topical formulation for sirolimus. Currently there is also no standard or commercially available topical formulation for everolimus. mTOR inhibitor can be formulated for topical administration as a solution, cream, ointment, dispersion, gel, or the like. Such formulations can be prepared in accordance with standard pharmaceutical formulation practices. See, for example, Remington’s Pharmaceutical Sciences, 17* Ed., 1985. For example, tablet form mTOR inhibitor can be ground into a powder and combined with a suitable pharmaceutically acceptable carrier.
  • Topical formulations generally include active pharmaceutical ingredient (mTOR inhibitor) in a concentration of about 0.01 to about 10.0 percent (w/w) or about 0.01 to about 10.0 percent (w/v).
  • the formulation includes mTOR inhibitor in a concentration of about 0.05 to about 5.0 percent (w/w) or about 0.05 to about 5.0 percent (w/v).
  • the formulation includes mTOR inhibitor in a concentration of about 0.1 to about 10.0 percent (w/w) or about 0.1 to about 10.0 percent (w/v).
  • the formulation includes mTOR inhibitor in a concentration of about 0.5 to about 5.0 percent (w/w) or about 0.5 to about 5.0 percent (w/v).
  • the formulation includes mTOR inhibitor in a concentration of about 0.1 to about 2.0 percent (w/w) or about 0.1 to about 2.0 percent (w/v).
  • the formulation includes mTOR inhibitor in a concentration of about 1.0 percent (w/w) or about 1.0 percent (w/v). In certain embodiments, the formulation includes mTOR inhibitor in a concentration of 1.0 percent (w/w) or 1.0 percent (w/v).
  • the formulation includes mTOR inhibitor in a concentration of about 2.0 percent (w/w) or about 2.0 percent (w/v). In certain embodiments, the formulation includes mTOR inhibitor in a concentration of 2.0 percent (w/w) or 2.0 percent (w/v).
  • Formulations in accordance with the invention can further include at least one additional pharmaceutically active agent.
  • a formulation in accordance with the invention can further include a PI3K inhibitor such as alpelisib, buparlisib, copanlisib, dactolisib, duvelisib, idelalisib, perifosine, pictilisib, taselisib, umbralisib, voxtalisib, AEZS-136, CAL263, CUDC-907, GNE-477, GSK
  • a PI3K inhibitor such as alpelisib, buparlisib, copanlisib, dactolisib, duvelisib, idelalisib, perifosine, pictilisib, taselisib, umbralisib, voxtalisib, AEZS-136, CAL263, CUDC-907, G
  • Dual mTQR/P1.3K inhibitors include without limitation dactolisib, BGT22.6,
  • Formulations in accordance with the invention can further include at least one additional agent selected from the group consisting of stabilizers, preservatives, colorants, fragrances, pH buffering agents, lubricants, penetration enhancers, texture enhancers, and the like.
  • compositions described just above can be provided as pharmaceutical compositions.
  • Such pharmaceutical compositions can be made by combining a
  • mTOR inhibitor pharmaceutically active amount of mTOR inhibitor and a pharmaceutically acceptable carrier suitable for topical administration.
  • mTOR inhibitor formulated for topical administration is administered up to four times a day to affected area or areas of skin. In certain embodiments, mTOR inhibitor formulated for topical administration is administered once a day. In certain embodiments, mTOR inhibitor formulated for topical administration is administered twice a day. In certain embodiments, mTOR inhibitor formulated for topical administration is administered three times a day. In certain embodiments, mTOR inhibitor formulated for topical administration is administered four times a day.
  • mTOR inhibitor formulated for topical administration is administered once every other day. In certain embodiments, mTOR inhibitor formulated for topical administration is administered once every three days. In certain embodiments, mTOR inhibitor formulated for topical administration is administered once every four days. In certain embodiments, mTOR inhibitor formulated for topical administration is administered once every five days. In certain embodiments, mTOR inhibitor formulated for topical administration is administered once every six days. In certain embodiments, mTOR inhibitor formulated for topical administration is administered once week.
  • Dosing frequency can be adjusted up or down based on clinical response to treatment.
  • Dosing can be based on preclinical and/or clinical experience as well as factors such as the nature and severity of the condition to be treated, skin integrity, other patient characteristics such as age and other medical conditions, and judgment of the prescribing physician or other health care provider.
  • This example describes a patient with biopsy-proven extensive non-LCH diagnosed with extensive BCH which clinically responded to twice daily application of 1% topical rapamycin ointment (compounded at a local pharmacy from tablets).
  • a 5-year-old Caucasian male presented to our clinic for a 3.5 year history of tan-pink macules and papules that began on his face at approximately 15 months of age.
  • a biopsy done from the left cheek at an outside facility was consistent with non-Langerhans cell histiocytosis (non- LCH). By 2.5 years of age, the lesions had progressed to involve the trunk and upper extremities.
  • Additional biopsies showed a diffuse dermal histiocytic and epithelioid cell infiltrate admixed with occasional neutrophils and eosinophils.
  • the infiltrate stained positive for CD68 and factor XHIa while CD la and S100 were negative, a pattern consistent with non-LCH.
  • BCH benign cephalic histiocytosis
  • Topical rapamycin (1%) compounded in ointment was initiated to the left face with the right face serving as a control.
  • Sirolimus blood levels were negative at 1 month.
  • non-LCH such as BCH
  • topical mTOR inhibitor such as rapamycin
  • inventor expects that all cutaneous involvement and cutaneous presentations of histiocytosis (Langerhans cell histiocytosis including histiocytosis X, eosinophilic granuloma, Letterer-Siwe disease, Hand-Schuller-Christian syndrome, and Hashimoto- Pritzker syndrome; non-LCH including juvenile xanthogranuloma, xanthoma
  • MRI/MRV revealed a low flow venolymphatic malformation confined to the subcutaneous fat with no visual draining veins. Clinically, it appeared most consistent with a mixed venolymphatic malformation, possibly with a small capillary component to it.
  • a 17-year-old female presented with several well demarcated pink to slightly tan patches with perilesional halos/rims of pallor scattered on her body, including one on her face. Many of those birthmarks were present since birth or at least since a very young age. The patient’s mother also had similar-appearing birthmarks. The patient was otherwise well. Genetic testing confirmed a pathogenic variant identified in RASA1 gene consistent with capillary malformation-arteriovenous malformation (CM-AVM) syndrome. Per the patient and her mother’s interest in a topical treatment, off-label use of topical 1% rapamycin cream was used twice a day to the lesion on the face.
  • CM-AVM capillary malformation-arteriovenous malformation
  • inventor expects that all topical mTOR inhibitors would produce a similar clinical improvement in the treatment all scars and keloids and all cutaneous proliferative or vascular conditions.

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des procédés pour le traitement d'affections vasculaires cutanées et d'affections prolifératives cutanées. Les procédés utilisent l'administration topique d'une cible mammifère d'inhibiteurs de la rapamycine (mTOR) tels que le sirolimus (rapamycine) et l'évérolimus. Les affections pouvant être traitées par les procédés décrites comprennent des malformations veinolymphatiques, de l'acné, de l'acné rosacée, de la dermatite périorificielle, de l'acné vulgaire, du syndrome de malformation capillaire- malformation artérioveineuse (MC-MAV) cutané, des RASopathies, de l'histiocytose langerhansienne, de l'histiocytose non langerhansienne, des cicatrices, des cicatrices hypertrophiques et chéloïdes, du syndrome de Protée, du spectre hypertrophique lié à PIK3CA (PROS), des syndromes tumoraux hamartomateux liés à PTEN, des malignités et des tumeurs cutanées associées aux mutations PI3K/AKT/mTOR, des kératodermies, de l'acanthosis nigricans, du syndrome de Birt-Hogg-Dubé, du syndrome de Brooke-Speigler, des cylindromes et du naevus épidermique. L'invention concerne également des formulations et des compositions pharmaceutiques ayant un inhibiteur de mTOR comme principe actif thérapeutique principal utile dans la mise en œuvre des procédés.
PCT/US2019/016758 2018-02-06 2019-02-06 Inhibiteurs de mtor topiques pour des affections prolifératives et vasculaires cutanées WO2019156999A1 (fr)

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US16/967,457 US12109199B2 (en) 2018-02-06 2019-02-06 Topical mTOR inhibitors for cutaneous proliferative and vascular conditions
US18/824,474 US20240423963A1 (en) 2018-02-06 2024-09-04 TOPICAL mTOR INHIBITORS FOR CUTANEOUS PROLIFERATIVE AND VASCULAR CONDITIONS

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US201862626779P 2018-02-06 2018-02-06
US62/626,779 2018-02-06

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020201073A1 (fr) * 2019-03-29 2020-10-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes de traitement de chéloïdes, de cicatrices hypertrophiques et/ou de troubles de l'hyperpigmentation

Citations (5)

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WO2008022256A2 (fr) * 2006-08-16 2008-02-21 Blagosklonny Mikhail V Procédés et compositions de prévention ou de traitement de maladies liées au vieillissement
US20130225631A1 (en) * 2010-06-24 2013-08-29 Joyce M.C. Teng Topical rapamycin for treatment of facial angiofibromas in tuberous sclerosis
WO2014177123A1 (fr) * 2013-04-30 2014-11-06 Melnik Bodo C Médicament contre l'acné et procédé pour sa préparation
US9555034B2 (en) * 2011-01-19 2017-01-31 The Trustees Of The University Of Pennsylvania Compositions and methods for treating skin cancer associated diseases
WO2018031789A1 (fr) * 2016-08-10 2018-02-15 The Board Of Regents Of The University Of Texas System Thérapie à base de rapamycine topique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008022256A2 (fr) * 2006-08-16 2008-02-21 Blagosklonny Mikhail V Procédés et compositions de prévention ou de traitement de maladies liées au vieillissement
US20130225631A1 (en) * 2010-06-24 2013-08-29 Joyce M.C. Teng Topical rapamycin for treatment of facial angiofibromas in tuberous sclerosis
US9555034B2 (en) * 2011-01-19 2017-01-31 The Trustees Of The University Of Pennsylvania Compositions and methods for treating skin cancer associated diseases
WO2014177123A1 (fr) * 2013-04-30 2014-11-06 Melnik Bodo C Médicament contre l'acné et procédé pour sa préparation
WO2018031789A1 (fr) * 2016-08-10 2018-02-15 The Board Of Regents Of The University Of Texas System Thérapie à base de rapamycine topique

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020201073A1 (fr) * 2019-03-29 2020-10-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes de traitement de chéloïdes, de cicatrices hypertrophiques et/ou de troubles de l'hyperpigmentation

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US20240423963A1 (en) 2024-12-26
US20210177810A1 (en) 2021-06-17

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